CN114829014A - Nanoscale topography system for DNA sequencing and method of making same - Google Patents

Nanoscale topography system for DNA sequencing and method of making same Download PDF

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CN114829014A
CN114829014A CN202080086305.2A CN202080086305A CN114829014A CN 114829014 A CN114829014 A CN 114829014A CN 202080086305 A CN202080086305 A CN 202080086305A CN 114829014 A CN114829014 A CN 114829014A
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bcp
layer
trench
domains
cylindrical
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CN114829014B (en
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N·佛米纳
G·布奇
C·约翰逊
N·P·克莱格
Y·S·申
K·加德拉布
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Robert Bosch GmbH
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Abstract

A method of fabricating a nanoscale topography system for inducing unfolding of DNA molecules for sequencing includes providing a substrate and creating trench walls on the substrate, the trench walls defining trenches therebetween. The method further comprises the following steps: depositing a layer of Block Copolymer (BCP) in the trench, and forming cylindrical domains by self-assembly of the BCP between the trench walls, removing a first portion of the cylindrical domains to create empty regions in the trench, and depositing a subsequent layer of BCP in said empty regions, and forming spherical domains by self-assembly of the BCP between the trench walls adjacent to a second portion of the cylindrical domains. The spherical domains form an interleaved column structure for unfolding DNA molecules, and the cylindrical domains form a parallel channel structure for entry of DNA molecules for sequencing.

Description

Nanoscale topography system for DNA sequencing and method of making same
Technical Field
Embodiments relate to a nanoscale topography system for DNA sequencing and methods of making the same.
Background
DNA is a central storage unit for genetic information, and extracting this information is a major goal in the field of biology. By gene sequencing, an insight into genomic variations, gene mutations and replication kinetics can be achieved. Over the past decades, sequencing technology has made tremendous progress in reading genetic information; however, the vision to extract the genetic code directly from a single long DNA molecule outside of a single cell has still met with limited success. Although human DNA has billions of base pairs, the direct reading of base pair sequences is hampered by the complex compaction of DNA within cells. Therefore, it is necessary to unfold and twist the soft aggregates of DNA to obtain the gene sequence.
Since DNA is extremely long (2.5 hundred million base pairs of human chromosomes have a complete extended length of about 8.5 cm), DNA is first sheared or enzymatically digested into fragments with a maximum length of several millimeters and incorporated into bacterial or yeast artificial chromosomes. Libraries of fragments of about 1000 base pairs can be directly sequenced and analyzed.
DNA linearization plays an important role in gene sequencing. Different techniques rely on hydrodynamic forces to achieve DNA extension. An attractive example is molecular combing. There, the salted coverslip is placed in a reservoir containing the DNA. During the residence of the cover slip in the reservoir, one or both ends of the DNA are attached to the cover slip surface. The coverslip was slowly withdrawn from the surface forming the gas-liquid meniscus. Capillary forces will stretch the DNA molecules. The technique is fast and relatively simple; however, it does not allow reliable manipulation of DNA fragments over several hundred microns in length.
In recent years, Chan et al (Genome Res.14, 1137-. Using hydrodynamic forces generated by the tapered microfluidic channel in laminar flow, the random coil conformation of DNA is stretched and stretched. In this setup, the solution is injected into the loading port and the sample solution is pressure driven into the chip and the labeled DNA molecules move with the flow in their random coil form. Downstream, the DNA unfolds as it interacts with the back field. These pre-stretched molecules are fully stretched in the tapered region under the influence of fluid dynamics. Short gradual elongations produce flow acceleration in distances comparable to the size of DNA. The resulting difference in flow velocity around different parts of the molecule will generate a force stretching it.
However, this large-scale morphology has proven to have limited effectiveness in stretching DNA molecules, as the stretch achieved will generally recover in the gap before the nanochannel. The real potential of single molecule sequencing requires miniaturized orders of magnitude of morphology (from micro-to nanochannels and columns), which presents new challenges in addressing nanometer-scale forces, complexity of nano-fabrication, and equipment cost.
Nanoscale morphologies can be achieved using complex techniques that differ in accuracy, cost, and throughput. For example, electron beam (e-beam) lithography is a process that uses focused electron beams to chemically alter the resist through the loss of energy produced by ionization. Feature resolution is limited to critical dimensions of about 3 nm due to scattering in the resist. In view of its impressive resolution, electron beam lithography is often used to fabricate nanochannels and holes, although it is a time consuming and expensive technique that is less suitable for exposing large areas across the wafer.
Focused Ion Beam (FIB) lithography, in which a focused ion beam (typically Ga) physically sputters neutral and ionized substrate atoms after impact, has also been used to fabricate nanochannels. The method is very versatile in that it can be used in conjunction with precursor gases for etching, imaging and depositing thin films (similar to chemical vapor deposition). However, it is more useful for prototyping than for patterning large areas.
Nanoimprint lithography can potentially address the requirements of high-throughput manufacturing. There, a well-designed counter template/mold is fabricated using electron beam lithography or other high resolution techniques. The template is pressed against a thin resist heated above its glass transition temperature. The resist is then cooled and the mold is removed. The uneven resist surface is then exposed to a directional etch in which thin regions are removed faster than thick regions, creating channels. The mold may be used multiple times to create multiple channels on multiple surfaces. Nevertheless, the mold erosion and flow behavior of the resist under compression has a negative impact on achieving small feature sizes.
SUMMARY
In one or more embodiments, a method of fabricating a nanoscale topography system for inducing unfolding of DNA molecules for sequencing includes providing a substrate and creating trench walls on the substrate, the trench walls defining trenches therebetween. The method further includes depositing a layer of Block Copolymer (BCP) in the trench, and forming cylindrical domains by self-assembly of the BCP between the trench walls, removing a first portion of the cylindrical domains to create empty regions in the trench, and depositing a subsequent layer of BCP in the empty regions, and forming spherical domains by self-assembly of the BCP between the trench walls adjacent to a second portion of the cylindrical domains. The spherical domains form an interleaved column structure for unfolding DNA molecules, and the cylindrical domains form a parallel channel structure for entry of DNA molecules for sequencing.
In one or more embodiments, a method of fabricating a nanoscale topography system for inducing unfolding of DNA molecules for sequencing includes providing a substrate and creating trench walls on the substrate, the trench walls defining trenches therebetween. The method further includes depositing a layer of a Block Copolymer (BCP) in the trench, and forming cylindrical domains by self-assembly of the BCP between trench walls, wherein the BCP comprises polystyrene-b-polydimethylsiloxane (PS-b-PDMS). The method further includes removing a first portion of the cylindrical domains to create empty regions in the trench, depositing a subsequent layer of BCP in the empty regions, and forming spherical domains by self-assembly of BCP between trench walls adjacent to a second portion of the cylindrical domains, and providing surface functionalization of at least one of the trenches and trench walls to control the positioning and orientation of the cylindrical domains and the spherical domains, wherein the surface functionalization is in preference to the major block of BCP. The spherical domains form an interleaved column structure for unfolding DNA molecules, and the cylindrical domains form a parallel channel structure for entry of DNA molecules for sequencing.
In one or more embodiments, a nanoscale topography system for inducing unfolding of DNA molecules for sequencing includes a substrate and trench walls on the substrate defining trenches therebetween. The system further comprises: a layer of Block Copolymer (BCP) deposited in the trench, the BCP self-assembling to form cylindrical domains between the trench walls; a void region in the trench formed by removing a first portion of the columnar region; and a subsequent layer of BCP deposited in the void region, the BCP self-assembling to form a spherical domain between trench walls adjacent to the second portion of the cylindrical domain. The spherical domains form an interleaved column structure for unfolding DNA molecules, and the cylindrical domains form a parallel channel structure for entry of DNA molecules for sequencing.
In one or more embodiments, the BCP comprises polystyrene-b-polydimethylsiloxane (PS-b-PDMS).
In one or more embodiments, the cylindrical domain comprises a plurality of planar inner cylinders.
In one or more embodiments, creating the trench walls includes depositing an anti-reflective coating (ARC) layer on the substrate, depositing a silicon dioxide layer on the ARC layer, and depositing a photoresist layer on the silicon dioxide layer.
In one or more embodiments, creating the trench walls further comprises creating a photoresist grating, and removing the silicon dioxide layer and the ARC layer.
In one or more embodiments, surface functionalization of at least one of the trench and the trench walls is used to control the positioning and orientation of the cylindrical domains and the spherical domains.
In one or more embodiments, surface functionalization is preferred over the main block of BCP.
In one or more embodiments, forming the columnar domains includes annealing the BCP layer to facilitate self-assembly, and etching the BCP layer to expose the columnar domains.
In one or more embodiments, removing the first portion of the columnar domains includes depositing a photoresist to cover the second portion of the columnar domains, and removing the first portion of the columnar domains by etching.
In one or more embodiments, forming the spherical domains includes annealing the subsequent BCP layer to facilitate self-assembly, and etching the subsequent BCP layer to expose the spherical domains.
In one or more embodiments, the method includes transferring the combined structure of cylindrical domains and spherical domains to a substrate.
In one or more embodiments, etching the BCP layer includes removing the PDMS top coat layer and the PS matrix of the layer to leave a plurality of in-plane PDMS cylinders, and etching the subsequent BCP layer includes removing the PDMS top coat layer and the PS matrix of the subsequent layer to leave a plurality of PDMS spherical domains.
In one or more embodiments, the substrate includes a sensing electrode.
Brief Description of Drawings
FIG. 1 is a schematic diagram illustrating template fabrication for a nanoscale topography system in accordance with one or more embodiments;
FIG. 2 is a schematic diagram showing the various steps of directed self-assembly of a cylindrical-forming block copolymer for fabricating a nanoscale topography system;
FIG. 3 is a schematic diagram showing the various steps of directed self-assembly of sphere-forming block copolymers for fabricating nanoscale topographical systems;
FIG. 4 is a schematic diagram of a nanoscale topography system for unfolding DNA (depicted as a series of beads entering an intermediate channel), according to one or more embodiments;
FIG. 5 is a graphical representation of finite element calculations of electric field distribution within a nanoscale topography system in accordance with one or more embodiments;
FIG. 6 is an enlarged view of the post/channel region shown in FIG. 5; and
FIG. 7 is a graph of electric field as a function of distance along the nanoscale topography system of FIGS. 5 and 6.
Detailed description of the invention
As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various and alternative forms. The drawings are not necessarily to scale; certain features may be exaggerated or minimized to show details of particular components. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention.
Unless explicitly indicated in the examples or otherwise, all numerical quantities in this description indicating amounts of material or conditions of reaction and/or use are to be understood as modified by the word "about". The first definition of an acronym or other abbreviation applies to all subsequent uses herein of the same abbreviation and applies mutatis mutandis to normal grammatical variations of the initially defined abbreviation; also, unless expressly stated to the contrary, measurement of a property depends on the same technique, whether referred to previously or later, with respect to the same property.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
It is also to be understood that this disclosure is not limited to the particular embodiments and methods described below, as specific components and/or conditions may, of course, vary. Furthermore, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting in any way.
It must also be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to a component in the singular is intended to comprise a plurality of components.
The terms "or" and "may be used interchangeably and may be understood to mean" and/or ".
The term "comprising" is synonymous with "including," having, "" containing, "or" characterized by. These terms are inclusive and open-ended, and do not exclude additional, unrecited elements or method steps.
The phrase "consisting of … …" excludes any element, step, or ingredient not specified in the claims. When the phrase appears in the clause of the subject matter of the claims, rather than immediately following the preamble, it is limited only to the elements set forth in the clause; other elements are not excluded from the claims as a whole.
The phrase "consisting essentially of … …" limits the scope of the claims to the specified materials or steps, plus those that do not materially affect the basic and novel feature(s) of the claimed subject matter.
The terms "comprising," "consisting of … …," and "consisting essentially of … …" may be used instead. When using one of these three terms, the subject matter disclosed and claimed herein can include using either of the other two terms.
Unless explicitly stated otherwise: percent, "parts" and ratio values are by weight; a group or class of materials is described as suitable or preferred for a given purpose in connection with the present disclosure, meaning that mixtures of any two or more members of the group or class are equally suitable or preferred; description of components in chemical terms refers to the components as they are added to any combination specified in the specification, and does not necessarily preclude chemical interactions between the components of the mixture once mixed.
It should also be understood that a range of integers explicitly includes all intervening integers. For example, integer ranges of 1-10 explicitly include 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. Similarly, the range 1-100 includes 1, 2, 3, 4 … … 97, 98, 99, 100. Similarly, where any range is desired, intervening numbers in increments of 10 divided by the difference between the upper and lower limits may be substituted for either the upper or lower limit. For example, if the range is 1.1 to 2.1, the following numbers 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0 may be selected as lower or upper limits.
In the examples described herein, concentrations, temperatures, and reaction conditions (e.g., pressure, pH, flow rates, etc.) may be practiced with ± 50% of the values indicated by the two significant figures rounded to or truncated to the values provided in the examples. In one refinement, the concentrations, temperatures, and reaction conditions (e.g., pressure, pH, flow rates, etc.) may be practiced with ± 30% of the values indicated by the two significant figures rounded to or truncated to the values provided in the examples. In another refinement, the concentrations, temperatures, and reaction conditions (e.g., pressure, pH, flow rates, etc.) may be practiced with ± 10% of the values indicated by the two significant figures rounded to or truncated to the values provided in the examples.
Throughout this application, where publications are referenced, the disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this disclosure pertains.
Next generation DNA sequencing requires nanoscale control of DNA. It is necessary to unfold the natural folded form of the DNA strand to gain access to each individual base in order to accurately decode the genetic information stored in the molecule. One promising way to achieve DNA spreading is to force the DNA through a lattice of pillars with a gap smaller than the unconstrained molecular size before entering the sensing region. The full potential of such methods requires efficient fabrication techniques to create a nanotopography system of pillars and channels.
The intrinsic mode of self-assembled Block Copolymers (BCP) provides a way to obtain such complex structures in the 10-100 nm length range, which are controlled by molecular chemistry and material processing conditions (deposition/spin coating, annealing and etching). In particular, directed self-assembly of single-layer BCPs minimizes defects, improves long-range order, and guides the formation of periodic lines and dots resulting from BCP microphase separation. The implementation of directed self-assembly of BCPs in the manufacture of DNA sequencing devices addresses many technical challenges in a relatively simple and cost-effective manner.
Thus, disclosed herein are manufacturing methods to create nanoscale topographic systems to induce DNA unfolding for DNA sequencing purposes. The fabrication method uses BCP as a masking technique to etch the pillar and via features into the substrate. The innate ability of BCPs to self-assemble into periodic patterns creates uniform domain sizes and controllable spacing, with the pattern and domain spacing of the repeating domains being controlled using polymer chemistry and polymer processing. The method employs directed self-assembly of BCP as an inexpensive and fast solution to create periodic nanoscale patterns with good long-range order.
BCP is a special class of soft materials in which the polymer chain contains more than one chemical species aggregated in a block. In its simplest form, a linear diblock copolymer resembles two polymer chains joined at one end. The limited miscibility of the constituent polymers in each block promotes phase separation, which reduces interfacial contact between blocks, while the arrangement of different blocks within the same molecule limits the degree of spatial separation, resulting in a periodic pattern rather than macroscopic phase separation. Spontaneous microphase separation of BCPs typically produces regions (grains) with short-range order microdomains, similar to polycrystalline structures, each grain having a different orientation and local defects. However, better control of the BCP sequence can be achieved using a guided chemistry and/or topography template formed on the substrate, a process known as directed self-assembly (DSA). Defect elimination and pattern alignment are defined by the template based on factors such as preferential surface wetting and the degree of fairness between BCP period and template size.
Among the different chemistries used in diblock copolymers, polystyrene-b-polydimethylsiloxane (PS-b-PDMS) shows great promise in nanoscale applications. A large degree of incompatibility between the two blocks promotes phase separation with a sharp interface. In addition, the process of exposing the polymer domains involves an oxygen plasma, which burns off the carbon based PS and converts the silicon based PDMS to silicon dioxide, creating a very stable glass pattern that can be used as a mask to etch the nanopatterns in the substrate. PS-b-PDMS can produce different domain shapes (spheres, cylinders, thin layers) depending on the ratio of its components.
One difficulty typically encountered with PS-b-PDMS is the migration of PDMS to the top free surface due to the low surface energy of PDMS compared to PS. This behavior creates in-plane motifs that limit the use of the layered structure for nanoscale patterns (a thin layer standing up can be etched to the substrate, but a thin layer lying down covers the entire substrate without a visible pattern). Thus, only spherical and cylindrical domains can be used as a mask. To control domain positioning and orientation, a one-dimensional constraint using grooves is implemented herein.
Although PS-b-PDMS is described herein in connection with the disclosed fabrication methods, it is understood that patterning by microphase separation is a general property of BCP, and thus, different combinations of BCP chemistries may alternatively be employed. Thus, the BCP can be any incompatible chemistry (e.g., PS-PDMS, PS-PMMA, PS-P4VP, etc.), but PS-PDMS is expected to perform well over a smaller length range due to the high degree of block incompatibility. If other chemistries are utilized, they should still have the polymer interface and stability of the final pattern needed to target smaller features.
Referring to fig. 1-4, the following fabrication steps may be used to create a nanotopography system 10 having an entry column 12 and a plurality of parallel channels 14 for inducing unfolding of DNA molecules for sequencing, in accordance with one or more embodiments. The process can be divided into three general sections: template fabrication, BCP self-assembly to form cylinders, and BCP self-assembly to form spheres. The schematic diagram shows a sequence of manufacturing steps that can be used to implement a pillar/via system using a BCP self-assembly pattern as a mask.
Referring to FIG. 1, template fabrication according to one or more embodiments is intended to create a template having a width of about, but not limited to, 200 nmThe trench 16 is elongated. First, an anti-reflective coating (ARC)18 can be deposited (e.g., by spin coating) on a pre-patterned substrate 20 (e.g., Si) with a sense electrode and then heated to induce crosslinking. Next, a silicon dioxide layer 22 (SiO) may be deposited 2 ) For example via electron beam evaporation. A photoresist 24 may then be deposited (e.g., spin coated) on top of the silicon dioxide layer 22 and heated. Using photolithography, a sample can be exposed by a laser-generated interference pattern, and post-exposure development can be used to produce a photoresist grating. Next, a reactive ion (e.g., CF) 4 Plasma) etching may be used to remove the silicon dioxide layer 22 (transfer the photoresist pattern into the silicon dioxide layer 22), and then O may be used 2 The + He plasma etch removes ARC layer 18 (transfers the pattern into ARC layer 18) to create stable trench walls 26 to guide the self-assembly of BCP. The trench walls 26 serve to guide the self-assembly of the pillar 12/channel 14 pattern, control the orientation of the channel 14, and bring the pillar 12 and channel 14 into close proximity, as further described below.
Next, the fabrication steps to create the topographic pattern for DNA unfolding are described. According to one or more embodiments, the application of BCP in the trench 16 between the trench walls 26 may follow a sequence of steps of deposition, annealing, and etching.
Turning to fig. 2, surface functionalization of the trenches 16 and/or trench walls 26 may be employed first to improve BCP wetting and improve overall order. In particular, the BCP planar inner cylinder has a natural tendency to align orthogonally with the trench walls 26. To promote parallel orientation of the cylinders, surface functionalization in preference to the main block (e.g., PS) may be used. Surface functionalization may include deposition (e.g., spin coating) of the predominant blocks onto the trench 16 and/or trench walls 26, thermal annealing, and rinsing to remove any ungrafted brush polymer.
With continued reference to fig. 2, directed self-assembly of BCPs forming a cylinder is illustrated. A BCP (e.g., PS-b-PDMS) layer 28 is deposited (e.g., spin-coated) in the trench 16 to a thickness that produces a single layer in-plane cylinder. Next, an annealing process is used to facilitate self-assembly. This may be achieved thermally or by solvent annealing in a solvent atmosphere. An etch may then be used that is,such as Reactive Ion Etching (RIE), the PDMS topcoat and PS matrix of the BCP monolayer 28 are removed to leave oxidized, in-plane PDMS cylinders 30. In particular, CF 4 Can be used to remove the PDMS layer formed on top of the BCP film, and O 2 Can be used for removing PS matrix. By exposing the BCP structure, a series of parallel cylinders 30 within the trench 16 is obtained. The channel structure 14 is thus created by a single layer of the planar inner cylinder 30. Alternatively, the channel structure 14 may be created by a template of thin layers standing upright.
Fig. 3 illustrates directed self-assembly of BCPs forming spheres. To position the post 12 adjacent the in-plane cylinder 30, the first portion 32 of the cylinder 30 may be removed. In one or more embodiments, a photoresist 24 may be applied and patterned to cover the trench 16 and the second portion 34 of the in-plane cylinder 30. The first portion 32 of the cylindrical domains 30 occupying the desired position of the pillars 12 may then be removed, for example by using CF 4 And (6) etching. By doing so, a generally flat void region 36 within the trench 16 may be restored, in which a spherical region 38 is located.
Similar to those used to create cylindrical BCP 30, BCP fabrication steps are employed to create spherical domains 38 (e.g., hexagons), including surface functionalization. A subsequent BCP layer (e.g., PS-b-PDMS) is deposited (e.g., spin coated) in the trench to a thickness that produces a monolayer of spherical domains. Next, an annealing process is used to facilitate self-assembly. This may be achieved thermally or by solvent annealing in a solvent atmosphere. Etching, such as Reactive Ion Etching (RIE), can then be used to remove the PDMS topcoat and PS matrix of the BCP monolayer to leave oxidized PDMS spherical domains 38. In particular, CF 4 Can be used to remove the surface coating PDMS layer formed on top of the BCP film, and O 2 Can be used to remove the PS matrix and subsequently oxidize the PDMS block to amorphous silica. By exposing the BCP structure, a single layer of spheres 38 within the trenches 16 is obtained, which act as the pillar structures 12. Alternatively, the post structure 12 may be produced from a template of vertically standing cylinders.
Referring again to fig. 3, the combined structure of the in-plane cylinder 30 and the sphere 38 may then be transferred to the silicon substrate 20, for example using RIE. According to a rule of notIn a limiting embodiment, the final depth of the silicon topography is on the same order of magnitude as the half-domain pitch of the cylinder in the plane. The BCP silica domain may use CF 4 And exposing and removing. In one non-limiting embodiment, the post 12 spacing and channel 14 width is about 10 nm.
FIG. 4 shows a schematic diagram of a final layout of the nanoscale topography system 10 for unfolding DNA for sequencing, according to one or more embodiments. As shown, the plurality of pillars 12 cause the DNA to unfold or unfold as the DNA is forced through the staggered pattern toward the channel 14. The DNA molecules can enter any of the parallel channels 14 to be read by a series of sensing electrodes 40.
Although hydrodynamic forces play an important role in driving DNA in microfluidic channels and causing DNA stretching, such forces are shielded as the channel topographic dimensions approach molecular dimensions. Application of an external electric field provides a controlled method of driving DNA. A linear relationship between the translocation speed of DNA and the external field has been demonstrated (Menard, L. D.& Ramsey, J. M., Anal. Chem.85, 1146 and 1153 (2013)), wherein the DNA velocity is higher in the wider channel. DNA mobility estimates show a strong effect of external forces compared to physical limitations. Nevertheless, the presence of the pillar structure in front of the nanochannel will alter the electric field distribution.
Fig. 5 and 6 plot electric fields of a representative column/channel topographic system (2 μm cell width) in accordance with one or more embodiments, where the electric fields drive charged DNA molecules through the topographic pattern. As shown, the electric field is relatively uniform (100V potential difference) near the left and right edges of the computing unit to which the computing electrodes are applied. A non-linear increase in field strength is observed near the column 12. In addition, a depletion region of low electric field is located near the pillar 12 along the horizontal axis. These regions will have evanescent forces that drive the DNA towards the nanochannel 14.
On the other hand, the concentrated field is oriented in the vertical direction. There, DNA is expected to experience a strong driving force along the field lines. Stagnation points are also observed at the entrance of the channel 14 along the horizontal axis. The alternating magnitude of the field values around the pillars 12 will exert a non-uniform force along the molecule, causing it to stretch and unfold or unfold. Outside the channel 14 entrance, the electric field in the nano-channel 14 takes a relatively constant value, thereby causing the DNA towards the channel 14 exit continuous drift. The DNA drift velocity can be determined by the field size to allow the sensing electrode to take the appropriate measurement time.
Fig. 7 is a graph of electric field as a function of distance along line a in fig. 6. The electric field localization is caused by the column structure, which is observed with a large field strength in the vertical direction. As shown in the cross-section along line a, there is a relatively uniform field strength inside the nanochannel.
Examples
Embodiments disclosed herein will now be described in more detail by way of examples thereof. It should be noted, however, that the present disclosure is not limited to these embodiments.
Template fabrication
An overview of the manufacturing process is given, wherein the protocol is followed according to the protocol described in the following documents: cheng, L.C.Et al, Nano Lett.18, 4360-4369 (2018)；Bai, W. Et al, Nano Lett.150925084648002 (2015); and Cheng, J. YEt al, appl. phys. Lett.81, 3657-3659 (2002)。
Anti-reflective coating (ARC) AZ BARLI @ (Merck KGaA) was first spin coated on pre-patterned substrates with sense electrodes and then baked on a hot plate at 175 ℃ for 60 seconds to induce crosslinking. Then depositing 20 nm SiO by electron beam evaporation 2 . 200 nm photoresist (PFI 88; Sumitomo Chemical Advanced Technologies) was spin coated on SiO 2 On top of the layer and baked on a hot plate at 90 ℃ for 60 seconds. The sample was exposed for several minutes by an interference pattern generated by a 2-beam coherent laser using a Lloyds mirror system. Post exposure development is used to produce a photoresist grating. Then CF 4 Plasma etching transfers photoresist patterns to SiO 2 In a layer of and O 2 The plasma transfers the pattern into the ARC layer to prepare stable trenches to guide the self-assembly of the BCP.
Fabrication of topographical patterns
The following provides fabrication steps to create a topographic pattern for DNA sequencing. The manufacturing sequence of steps follows Tavakkoli k, g.Et al, nat. Commun.7, 1-10 (2016)The above-mentioned processes are described.
Cylindrical domains
Surface functionalization
For the application of the PS brush (main block), 1.2 kg mol are added −1 A 1 wt% solution of hydroxyl terminated PS (Polymer Source, Inc.) in propylene glycol monomethyl ether acetate was spin coated at 3000 r.p.m. for 30 seconds. The substrate was thermally annealed in a vacuum oven (20 mtorr) at 170 ℃ for 15 hours, then immersed in a room temperature toluene bath for 15 minutes and rinsed with toluene to remove any ungrafted brush polymer.
Spin coating
For PS-b-PDMS polymer formed into a cylinder, 45.5 kg mol −1 Weight Polymer (f) PDMS =32%, PDI (polydispersity index) about 1.09) was dissolved in propylene glycol monomethyl ether acetate at 2 wt% for spin coating. The equilibrium domain spacing for this molecular weight is about 30 nm. The dissolved BCP was spin coated on the patterned substrate to the thickness of the in-plane cylinder that produced the monolayer.
Annealing
Annealing may be achieved as follows: the sample was thermally placed in a vacuum oven at 150 ℃ for 16 hours, or solvent annealed in a solvent atmosphere. Specifically, BCP was annealed in a covered glass beaker containing 2 ml of toluene for 5-6 hours, and then immediately quenched in ambient air to freeze the annealed structure.
Etching of
Reactive Ion Etching (RIE) was used to remove the PDMS topcoat of the BCP monolayer and the PS matrix to leave oxidized in-plane PDMS cylinders. Particularly, 5 seconds of CF 4 (50W, 15 mTorr) for removal of the PDMS layer formed on top of the BCP film, and 22 seconds of O 2 (90W, 6 mTorr) was used to remove the PS matrix.
Spherical domains
To position the pillars near the in-plane cylinder, a photoresist is applied and patterned to cover the trenches and a portion of the in-plane cylinder. Using CF 4 The cylindrical domains occupying the pillar positions are removed.
Spin coating
BCP fabrication steps (similar to those of cylindrical BCPs) are used to create hexagonal spherical domains, which include surface functionalization (gadelab, k.Et al, Nano Lett.18, 3766-3772 (2018)). In particular, PS-b-PDMS (small volume fraction f) PDMS = 16.5%, molecular weight 51.5 kg/mol, PDI = 1.04, 1 wt% in PGMEA) was spin coated to a thickness of 38 nm.
Annealing
The sample was annealed in a chamber of a mixed solvent of toluene and heptane (volume ratio 5:1) at room temperature for 30 seconds, and then thermally quenched at 60 ℃ for 5 seconds. The sample was then removed from the annealing chamber within a few seconds.
Etching of
After annealing, 5 seconds of CF was used 4 (50W, 15 mTorr), followed by 22 seconds of O 2 A reactive ion etch process (90W, 6 mtorr) to remove the surface coating PDMS layer and the PS matrix, and then oxidize the PDMS blocks to amorphous silica.
RIE was used to transfer the combined structure of planar inner cylinders and hexagonal spheres into a silicon substrate. CF may be used 4 The BCP silicon dioxide domains are exposed and removed.
While exemplary embodiments are described above, these embodiments are not intended to describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation, and it is understood that various changes may be made without departing from the spirit and scope of the invention. In addition, features of various implementing embodiments may be combined to form further embodiments of the invention.

Claims (20)

1. A method of making a nanoscale topography system for inducing unfolding of DNA molecules for sequencing, the method comprising:
providing a substrate;
creating trench walls on a substrate, the trench walls defining a trench therebetween;
depositing a layer of Block Copolymer (BCP) in the trench and forming cylindrical domains by self-assembly of BCP between the trench walls,
removing a first portion of the columnar areas to create empty areas in the trench; and
depositing a subsequent layer of BCP in the void region and forming a spherical region by self-assembly of BCP between trench walls adjacent to the second portion of the cylindrical region,
wherein the spherical domains form an interleaved column structure for unfolding a DNA molecule and the cylindrical domains form a parallel channel structure for entry of a DNA molecule for sequencing.
2. The method of claim 1, wherein the BCP comprises polystyrene-b-polydimethylsiloxane (PS-b-PDMS).
3. The method of claim 1, wherein the cylindrical domain comprises a plurality of planar inner cylinders.
4. The method of claim 1, wherein creating the trench walls comprises depositing an anti-reflective coating (ARC) layer on the substrate, depositing a silicon dioxide layer on the ARC layer, and depositing a photoresist layer on the silicon dioxide layer.
5. The method of claim 4, wherein creating trench walls further comprises creating a photoresist grating, and removing the silicon dioxide layer and the ARC layer.
6. The method of claim 1, further comprising providing surface functionalization of at least one of the trench and the trench walls to control the positioning and orientation of the cylindrical domains and the spherical domains.
7. The method of claim 6, wherein surface functionalization is in preference to the main block of BCP.
8. The method of claim 1, wherein forming the columnar domains comprises annealing the BCP layer to promote self-assembly, and etching the BCP layer to expose the columnar domains.
9. The method of claim 1, wherein removing the first portion of the columnar areas comprises depositing a photoresist to cover the second portion of the columnar areas, and removing the first portion of the columnar areas by etching.
10. The method of claim 1, wherein forming spherical domains comprises annealing a subsequent BCP layer to promote self-assembly, and etching the subsequent BCP layer to expose spherical domains.
11. The method of claim 1, further comprising transferring the combined structure of cylindrical and spherical domains to a substrate.
12. A method of making a nanoscale topography system for inducing unfolding of DNA molecules for sequencing, the method comprising:
providing a substrate;
creating trench walls on a substrate, the trench walls defining a trench therebetween;
depositing a layer of Block Copolymer (BCP) in the trench and forming cylindrical domains by self-assembly of the BCP between the trench walls, wherein the BCP comprises polystyrene-b-polydimethylsiloxane (PS-b-PDMS);
removing a first portion of the columnar areas to create empty areas in the trench;
depositing a subsequent layer of BCP in the void region and forming a spherical region by self-assembly of BCP between trench walls adjacent to the second portion of the cylindrical region; and
providing surface functionalization of at least one of the trench and the trench walls to control the positioning and orientation of the cylindrical domains and the spherical domains, wherein the surface functionalization is preferential over the main block of BCP,
wherein the spherical domains form an interleaved column structure for unfolding a DNA molecule and the cylindrical domains form a parallel channel structure for entry of a DNA molecule for sequencing.
13. The method of claim 12, wherein removing the first portion of the columnar areas comprises depositing a photoresist to cover the second portion of the columnar areas, and removing the first portion of the columnar areas by etching.
14. The method of claim 12, wherein forming cylindrical domains comprises annealing a BCP layer to promote self-assembly, and etching the BCP layer to expose cylindrical domains, and wherein forming spherical domains comprises annealing a subsequent BCP layer to promote self-assembly, and etching the subsequent BCP layer to expose spherical domains.
15. The method of claim 14, wherein etching the BCP layer comprises removing the PDMS top coat and the PS matrix of the layer to leave a plurality of in-plane PDMS cylinders, and etching the subsequent BCP layer comprises removing the PDMS top coat and the PS matrix of the subsequent layer to leave a plurality of PDMS spherical domains.
16. A nanoscale topography system for inducing unfolding of DNA molecules for sequencing, the system comprising:
a substrate;
trench walls on the substrate, the trench walls defining a trench therebetween;
a layer of a Block Copolymer (BCP) deposited in the trench, the block copolymer self-assembling to form cylindrical domains between the trench walls,
a void region in the trench formed by removing a first portion of the columnar region; and
a subsequent layer of BCP deposited in the void region, the BCP self-assembling to form a spherical domain between trench walls adjacent to a second portion of the cylindrical domain,
wherein the spherical domains form an interleaved column structure for unfolding a DNA molecule and the cylindrical domains form a parallel channel structure for entry of a DNA molecule for sequencing.
17. The system of claim 16, wherein the BCP comprises polystyrene-b-polydimethylsiloxane (PS-b-PDMS).
18. The system of claim 16, wherein at least one of the trench and the trench walls comprises surface functionalization to control the positioning and orientation of cylindrical domains and spherical domains.
19. The system of claim 18, wherein surface functionalization is in preference to the main block of BCP.
20. The system of claim 16, wherein the substrate comprises a sensing electrode.
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